THC has mild to moderate analgesic effects, and cannabis can be used to treat pain by altering transmitter release on dorsal root ganglion of the spinal cord and in the periaqueductal gray.[15] Other effects include relaxation, alteration of visual, auditory, and olfactory senses, fatigue, and appetite stimulation. THC has marked antiemetic properties. It may acutely reduce aggression and increase aggression during withdrawal.[16]

Due to its partial agonistic activity, THC appears to result in greater downregulation of cannabinoid receptors than endocannabinoids, further limiting its efficacy over other cannabinoids. While tolerance may limit the maximal effects of certain drugs, evidence suggests that tolerance develops irregularly for different effects with greater resistance for primary over side-effects, and may actually serve to enhance the drug's therapeutic window.[17] However, this form of tolerance appears to be irregular throughout mouse brain areas. THC, as well as other cannabinoids that contain a phenol group, possesses mild antioxidant activity sufficient to protect neurons against oxidative stress, such as that produced by glutamate-induced excitotoxicity.[18]

It has long been known that, in humans, cannabis increases appetite and consumption of food. The mechanism for appetite stimulation in subjects is believed to result from activity in the gastro-hypothalamic axis. CB1 activity in the hunger centers in the hypothalamus increases the palatability of food when levels of a hunger hormone ghrelin increase prior to consuming a meal. After chyme is passed into the duodenum, signaling hormones such as cholecystokinin and leptin are released, causing reduction in gastric emptying and transmission of satiety signals to the hypothalamus. Cannabinoid activity is reduced through the satiety signals induced by leptin release.

A study in mice suggested that based on the connection between palatable food and stimulation of dopamine (DA) transmission in the shell of the nucleus accumbens (NAc), cannabis may not only stimulate taste, but possibly the hedonic (pleasure) value of food as well. The study later demonstrates habitual use of THC lessening this heightened pleasure response, indicating a possible similarity in humans.[19] The inconsistency between DA habituation and enduring appetite observed after THC application suggests that cannabis-induced appetite stimulation is not only mediated by enhanced pleasure from palatable food, but through THC stimulation of another appetitive response as well.

The discovery of THC by a team of researchers from Hebrew University Pharmacy School was first described in "Isolation, structure and partial synthesis of an active constituent of hashish", published in the Journal of the American Chemical Society in 1964.[8] Research was also published in the academic journal Science, with "Marijuana chemistry" by Raphael Mechoulam in June 1970,[20] In the latter, the team of researchers from Hebrew University and Tel Aviv University experimented on monkeys to isolate the active compounds in hashish. Their results provided evidence that, except for tetrahydrocannabinol, no other major active compounds were present in hashish.

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In April 2014 the American Academy of Neurology published a systematic review of the efficacy and safety of medical marijuana and marijuana-derived products in certain neurological disorders.[21] The review identified 34 studies meeting inclusion criteria, of which 8 were rated as Class I quality.[21] The study found evidence supporting the effectiveness of cannabis extracts and THC in treating certain symptoms of multiple sclerosis, but found insufficient evidence to determine the effectiveness of cannabis products in treating several other neurological diseases.[21]

Spasticity. Based on the results of 3 high quality trials and 5 of lower quality, oral cannabis extract was rated as effective, and THC as probably effective, for improving patient's subjective experience of spasticity. Oral cannabis extract and THC both were rated as possibly effective for improving objective measures of spasticity.[21]

Centrally mediated pain and painful spasms. Based on the results of 4 high quality trials and 4 low quality trials, oral cannabis extract was rated as effective, and THC as probably effective in treating central pain and painful spasms.[21]

Bladder dysfunction. Based on a single high quality study, oral cannabis extract and THC were rated as probably ineffective for controlling bladder complaints in multiple sclerosis[21]

Huntington disease. No reliable conclusions could be drawn regarding the effectiveness of THC or oral cannabis extract in treating the symptoms of Huntington disease as the available trials were too small to reliably detect any difference[21]

Parkinson disease. Based on a single study, oral cannabis extract was rated probably ineffective in treating levodopa-induced dyskinesia in Parkinson disease.[21]

Alzheimer's disease. A 2011 Cochrane Review found insufficient evidence to conclude whether cannabis products have any utility in the treatment of Alzheimer's disease.[22]

There has never been a documented human fatality solely from overdosing on tetrahydrocannabinol or cannabis in its natural form.[31] However, numerous reports have suggested an association of cannabis smoking with an increased risk of myocardial infarction,[32][33] also known as a heart attack. Information about the toxicity of THC is primarily based on results from animal studies. The toxicity depends on the route of administration and the laboratory animal.

The estimated lethal dose of intravenous dronabinol in humans is 30 mg/kg,[34] meaning lethality is unlikely. The typical medicinal dosage administered is two 2.5 mg capsules daily; for an 80 kg man (~170 lb). A lethal dose for such a person would be 960 of those capsules infused intravenously. Non-fatal overdoses have occurred: "Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules."[34]

A meta analysis of cannabis and THC clinical trials conducted by the American Academy of Neurology found that of 1619 persons treated with cannabis products (including some treated with smoked cannabis and nabiximols), 6.9% discontinued due to side effects, compared to 2.2% of 1,118 treated with placebo. Detailed information regarding side effects was not available from all trials, but nausea, increased weakness, behavioral or mood changes, suicidal ideation, hallucinations, dizziness, and vasovagal symptoms, fatigue, and feelings of intoxication were each described as side effects in at least 2 trials. There was a single death rated by the investigator as "possibly related" to treatment. This person had a seizure followed by aspiration pneumonia. The paper does not describe whether this was one of the patients from the epilepsy trials.[21]

Its status as an illegal drug in most countries can make research difficult; for instance in the United States where the National Institute on Drug Abuse was the only legal source of cannabis for researchers until it recently became legalized in Colorado, Washington state, Oregon, Alaska, and Washington D.C.[35]

A 2011 systematic review evaluated published studies of the acute and long-term cognitive effects of cannabis. THC intoxication is well established to impair cognitive functioning on an acute basis, including effects on the ability to plan, organize, solve problems, make decisions, and control impulses. The extent of this impact may be greater in novice users, and paradoxically, those habituated to high level ingestion may have reduced cognition during withdrawal. Studies of long-term effects on cognition have provided conflicting results, with some studies finding no difference between long-term abstainers and never-users and others finding long-term deficits. The discrepancies between studies may reflect greater long-term effects among heavier users relative to occasional users, and greater duration of effect among those with heavy use as adolescents compared to later in life.[36] A second systematic review focused on neuroimaging studies found little evidence supporting an effect of cannabis use on brain structure and function.[37] A 2003 meta analysis concluded that any long-term cognitive effects were relatively modest in magnitude and limited to certain aspects of learning and memory.[38]

A 2007 meta analysis concluded that cannabis use reduced the average age of onset of psychosis by 2.7 years relative to non-cannabis use.[39] A 2005 meta analysis concluded that adolescent use of cannabis increases the risk of psychosis, and that the risk is dose-related.[40] A 2004 literature review on the subject concluded that cannabis use is associated with a two-fold increase in the risk of psychosis, but that cannabis use is "neither necessary nor sufficient" to cause psychosis.[41] A French review from 2009 came to a conclusion that cannabis use, particularly that before age 15, was a factor in the development of schizophrenic disorders.[42]

Some studies have suggested that cannabis users have a greater risk of developing psychosis than non-users. This risk is most pronounced in cases with an existing risk of psychotic disorder.[43][44] A 2005 paper from the Dunedin study suggested an increased risk in the development of psychosis linked to polymorphisms in the COMT gene.[45] However, a more recent study cast doubt on the proposed connection between this gene and the effects of cannabis on the development of psychosis.[46]

A 2008 German review reported that cannabis was a causal factor in some cases of schizophrenia and stressed the need for better education among the public due to increasingly relaxed access to cannabis.[47]

THC, 11-OH-THC and THC-COOH can be detected and quantitated in blood, urine, hair, oral fluid or sweat using a combination of immunoassay and chromatographic techniques as part of a drug use testing program or in a forensic investigation of a traffic or other criminal offense or suspicious death.[49][50][51]

Cannabidiol, the second most abundant cannabinoid found in cannabis, is an indirect antagonist against cannabinoid agonists; thus reducing the effects of anandamide and THC agonism on the CB1 and CB2 receptors.

The presence of these specialized cannabinoid receptors in the brain led researchers to the discovery of endocannabinoids, such as anandamide and 2-arachidonoyl glyceride (2-AG). THC targets receptors in a manner far less selective than endocannabinoid molecules released during retrograde signaling, as the drug has a relatively low cannabinoid receptor efficacy and affinity. In populations of low cannabinoid receptor density, THC may act to antagonize endogenous agonists that possess greater receptor efficacy.[17] THC is a lipophilic molecule[55] and may bind non-specifically to a variety of entities in the brain and body, such as adipose tissue (fat).[56][57]

THC is metabolized mainly to 11-OH-THC by the body. This metabolite is still psychoactive and is further oxidized to 11-nor-9-carboxy-THC (THC-COOH). In humans and animals, more than 100 metabolites could be identified, but 11-OH-THC and THC-COOH are the dominating metabolites. Metabolism occurs mainly in the liver by cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A4.[59] More than 55% of THC is excreted in the feces and ~20% in the urine. The main metabolite in urine is the ester of glucuronic acid and THC-COOH and free THC-COOH. In the feces, mainly 11-OH-THC was detected.[60]

Dronabinol is the INN for a pure isomer of THC, (–)-trans-Δ9-tetrahydrocannabinol,[64] which is the main isomer found in cannabis. Synthesized dronabinol is marketed as Marinol[65] (a registered trademark of Solvay Pharmaceuticals). Dronabinol is also marketed, sold, and distributed by PAR Pharmaceutical Companies under the terms of a license and distribution agreement with SVC pharma LP, an affiliate of Rhodes Technologies. Synthesized THC may be generally referred to as dronabinol. It is available as a prescription drug (under Marinol[66]) in several countries including the United States, Germany, South Africa and Australia.[67] In the United States, Marinol is a Schedule III drug, available by prescription, considered to be non-narcotic and to have a low risk of physical or mental dependence. Efforts to get cannabis rescheduled as analogous to Marinol have not succeeded thus far, though a 2002 petition has been accepted by the DEA. As a result of the rescheduling of Marinol from Schedule II to Schedule III, refills are now permitted for this substance. Marinol has been approved by the U.S. Food and Drug Administration (FDA) in the treatment of anorexia in HIV/AIDS patients, as well as for refractory nausea and vomiting of patients undergoing chemotherapy, which has raised much controversy[68] as to why natural THC is considered a schedule I drug.[69]

An analog of dronabinol, nabilone, is available commercially in Canada under the trade name Cesamet, manufactured by Valeant Pharmaceuticals. Cesamet has also received FDA approval and began marketing in the U.S. in 2006. Nabilone is a Schedule II drug.[71]

It takes over one hour for Marinol to reach full systemic effect,[74] compared to seconds or minutes for smoked or vaporized cannabis.[75] Some patients accustomed to inhaling just enough cannabis smoke to manage symptoms have complained of too-intense intoxication from Marinol's predetermined dosages[citation needed]. Many patients have said that Marinol produces a more acute psychedelic effect than cannabis, and it has been speculated that this disparity can be explained by the moderating effect of the many non-THC cannabinoids present in cannabis.[citation needed] For that reason, alternative THC-containing medications based on botanical extracts of the cannabis plant such as nabiximols are being developed. Mark Kleiman, director of the Drug Policy Analysis Program at UCLA's School of Public Affairs said of Marinol, "It wasn't any fun and made the user feel bad, so it could be approved without any fear that it would penetrate the recreational market, and then used as a club with which to beat back the advocates of whole cannabis as a medicine."[76] Mr. Kleiman's opinion notwithstanding, clinical trials comparing the use of cannabis extracts with Marinol in the treatment of cancer cachexia have demonstrated equal efficacy and well-being among patients in the two treatment arms.[77] United States federal law currently registers dronabinol as a Schedule III controlled substance, but all other cannabinoids remain Schedule I, except synthetics like nabilone.[78]

Since at least 1986, the trend has been for THC in general, and especially the Marinol preparation, to be downgraded to less and less stringently-controlled schedules of controlled substances, in the U.S. and throughout the rest of the world.

An article published in the April–June 1998 issue of the Journal of Psychoactive Drugs found that "Healthcare professionals have detected no indication of scrip-chasing or doctor-shopping among the patients for whom they have prescribed dronabinol". The authors state that Marinol has a low potential for abuse.[80]

At its 33rd meeting, in 2003, the World Health Organization Expert Committee on Drug Dependence recommended transferring THC to Schedule IV of the Convention, citing its medical uses and low abuse potential.[82]

^Marlowe, Douglas B. (December 2010). "The Facts On Marijuana". NADCP. Based upon several nationwide epidemiological studies, marijuana’s dependence liability has been reliably determined to be 8 to 10 percent.

^"Tetrahydrocannabinol – Compound Summary". National Center for Biotechnology Information. PubChem. Retrieved 12 January 2014. Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%.

^Grotenhermen, Franjo; Russo, Ethan, eds. (2002). "Review of Therapeutic Effects". Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. New York City: Psychology Press. p. 124. ISBN978-0-7890-1508-2. The only approved preparations to date, Marinol (dronabinol, Δ9-THC) and Cesamet (nabilone), are approved for the indication of nausea and vomiting associated with cancer chemotherapy. Marinol is also approved for anorexia and cachexia in HIV/AIDS.

^Ashton CH (February 2001). "Pharmacology and effects of cannabis: a brief review". Br J Psychiatry178 (2): 101–106. doi:10.1192/bjp.178.2.101. PMID11157422. Because they are extremely lipid soluble, cannabinoids accumulate in fatty tissues, reaching peak concentrations in 4–5 days. They are then slowly released back into other body compartments, including the brain. ... Within the brain, THC and other cannabinoids are differentially distributed. High concentrations are reached in neocortical, limbic, sensory and motor areas.